Macrocycles as factor XIa inhibitors

Abstract

The present invention provides compounds of Formula (I): or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

What is claimed is: 
     
       1. A compound of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 ring A is phenyl; 
 ring B is oxazolyl; 
 ring C is phenyl; 
 L 1  is independently selected from the group consisting of: a bond, —CHR 5 —, —CHR 5 CHR 5 —, —CR 5 ═CR 5 —, —C≡C—, —OCH 2 —, —CHR 5 NH—, —CH 2 O—, —SCH 2 —, —SO 2 CH 2 —, —CH 2 NH—, and —CR 5 R 5 —; 
 L is independently selected from the group consisting of: —C 1-6  alkylene-(aryl)-C 0-4  alkylene-, and —C 1-6  alkylene-(5- to 6-membered heterocycle)-C 0-4  alkylene-; wherein said heterocycle comprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4  alkyl), O, and S(O) p ; wherein said alkylene is substituted with 0-2 R 7  and optionally one or more of the carbon atoms of said alkylene may be replaced by O, S, NH, N(C 1-4  alkyl), CO, CONH, NHCO, OCONH, NHCO 2 , SO 2 NH, NHSO 2 , CON(C 1-4  alkyl), or N(C 1-4  alkyl)CO; wherein said aryl and heterocycle are substituted with 0-2 R 7a ; 
 Y is independently selected from the group consisting of: CH 2 , CH(C 1-4  alkyl), C(C 1-4  alkyl) 2 , O, S, NH, N(C 1-4  alkyl), N(CO 2 (C 1-4  alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4  alkyl)CH 2 —, —OCONH—, —OCON(C 1-4  alkyl)-, —NHCONH—, —SO 2 NH—, —NHCO 2 —, and —NHSO 2 —; 
 R 1  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-6  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, OH, C 1-4 haloalkyl, OCH 2 F, OCHF 2 , OCF 3 , CN, NH 2 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , —CO 2 (C 1-4  alkyl), —CO(C 1-4  alkyl), —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4  alkyl), —CH 2 NHCO 2 (C 1-4  alkyl), —OCH 2 CO 2 H, —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —C(═NH)NH 2 , and phenyl substituted with 0-2 R a ; 
 R 2  is independently a 5- to 7-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4  alkyl), O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2a ; 
 R 2a  is independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, —CH 2 OH, C 1-4  alkoxy, OH, CF 3 , OCF 3 , CN, NH 2 , CO 2 H, CO 2 (C 1-4  alkyl), COC 1-4  alkyl, —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —SO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), and —SO 2 N(C 1-4  alkyl) 2 ; 
 R 3  is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4  alkyl, C 1-4  alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), —C(O)NH 2 , —C(O)NH(C 1-4  alkyl), —C(O)N(C 1-4  alkyl) 2 , —CH 2 CO 2 H, and C 3-6  cycloalkyl; 
 R 4  is independently selected from the group consisting of: H, and C 1-4  alkyl; 
 R 5  is, independently at each occurrence, selected from the group consisting of: H, halogen, OH, and C 1-4  alkyl; 
 R 6  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4  alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4  alkyl), —(CH 2 ) 2 CO 2 (C 1-4  alkyl), NH 2 , NH(C 1-4 alkyl), —CH 2 NH 2 , —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4  alkyl), —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4  alkyl), —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH 2 , —SO 2 NH(C 1-4  alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), —C(O)NH(CH 2 ) 2 O(C 1-4 alkyl), —CONH 2 , —CONH(C 1-4  alkyl), —CON(C 1-4  alkyl) 2 , —CH 2 CONH 2 , and 
 
       
         
           
           
               
               
           
         
         R 7  and R 7a  are, independently at each occurrence, selected from the group consisting of: halogen, OH, NH 2 , CH 2 NH 2 , CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , —NH(C 1-4  alkyl), —N(C 1-4  alkyl) 2 , C 1-4  alkoxy, CH 2 OH, CH 2 O(C 1-4  alkyl), CH 2 O(CH 2 ) 1-4 O(C 1-4  alkyl), CO 2 H, CO 2 (C 1-4  alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , —OCO(C 1-4  alkyl), —CON(C 1-4  alkyl)(CH 2 ) 2 N(C 1-4  alkyl) 2 , C 1-4  alkyl, —(CO) 0-1 (CH 2 ) 0-1 -aryl, and —(CO) 0-1 (CH 2 ) 0-1 -(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4  alkyl), O, and S(O) p ; wherein said aryl and heterocycle are substituted with 0-2 R 8 ; 
         R 8  is, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , C 1-4  alkoxy, CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), CONH 2 , and C 1-4  alkyl; 
         R 9  is a 4- to 6-membered heterocycle comprising: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4  alkyl), N(CO 2 (C 1-4  alkyl)), O, and S(O) p ; 
         R a  is, independently at each occurrence, selected from the group consisting of: halogen, OH, CF 3 , C 1-4  alkoxy, and C 1-4  alkyl; 
         p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2. 
       
     
     
       2. The compound of  claim 1 , or a stereoisomer, a tautomer, a
 pharmaceutically acceptable salt thereof, wherein: 
 ring A is phenyl; 
 
       
         
           
           
               
               
           
         
       
       and 
       
         
           
           
               
               
           
         
       
     
     
       3. A compound of Formula (II): 
       
         
           
           
               
               
           
         
       
       or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         L 1  is independently selected from the group consisting of: a bond, —CHR 5 CHR 5 —, —CR 5 ═CHR 5 —, —C≡C—, —OCH 2 —, —CHR 5 NH—, —CH 2 O—, —SCH 2 —, —SO 2 CH 2 —, —CH 2 NH—, and —CR 5 R 5 —; 
         L is independently selected from the group consisting of: —C 1-6  alkylene-(aryl)-C 0-4  alkylene-, and —C 1-6  alkylene-(5- to 6-membered heterocycle)-C 0-4  alkylene-; wherein said heterocycle comprises: carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4  alkyl), O, and S(O) p ; wherein said alkylene is substituted with 0-2 R 7  and optionally one or more of the carbon atoms of said alkylene may be replaced by O, S, NH, N(C 1-4  alkyl), CO, CONH, NHCO, OCONH, SO 2 NH, or CON(C 1-4  alkyl); wherein said aryl and heterocycle are substituted with 0-2 R 7a ; 
         Y is independently selected from the group consisting of: CH 2 , CH(C 1-4  alkyl), C(C 1-4  alkyl) 2 , O, S, NH, N(C 1-4  alkyl), N(CO 2 (C 1-4  alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4  alkyl)CH 2 —, —OCONH—, —OCON(C 1-4  alkyl)-, —NHCONH—, and —SO 2 NH—; 
         R 1  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-6  alkyl, C 1-4  alkoxy, C 1-4  alkylthio, OH, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , CN, NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , CO 2 (C 1-4  alkyl), CO(C 1-4  alkyl), —OCH 2 CO 2 H, —CH 2 NH 2 , —CONH 2 , —CONH(C 1-4  alkyl), —CH 2 NHCO 2 (C 1-4  alkyl), —SO 2 NH 2 , and —C(═NH)NH 2 ; 
         R 2  is independently a 5- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, O, and S(O) p , wherein said heterocycle is substituted with 0-2 R 2a ; 
         R 2a  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, —CH 2 OH, C 1-4  alkoxy, OH, CF 3 , OCF 3 , CN, NH 2 , CO 2 H, CO 2 (C 1-4  alkyl), COC 1-4  alkyl, —CONH 2 , —CONH(C 1-4  alkyl), and —CON(C 1-4  alkyl) 2 ; 
         R 3  is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4  alkyl, C 1-4  alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), —C(O)NH 2 , —C(O)NH(C 1-4  alkyl), —C(O)N(C 1-4  alkyl) 2 , and —CH 2 CO 2 H; 
         R 4  is independently selected from the group consisting of: H and C 1-4  alkyl; 
         R 5  is, independently at each occurrence, selected from the group consisting of: H, halogen, OH, and C 1-4  alkyl; 
         R 6  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4  alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4  alkyl), —(CH 2 ) 2 CO 2 (C 1-4  alkyl), NH 2 , NH(C 1-4 alkyl), —CH 2 NH 2 , —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4  alkyl), —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4  alkyl), —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), —C(O)NH(CH 2 ) 2 O(C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , —CH 2 CONH 2 , and 
       
       
         
           
           
               
               
           
         
         R 7  and R 7a  are, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , N(C 1-4  alkyl) 2 , C 1-4  alkoxy, CH 2 OH, CH 2 O(C 1-4  alkyl), CO 2 H, CO 2 (C 1-4  alkyl), CH 2 CO 2 H, CH 2 CO 2 (C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , —OCO(C 1-4  alkyl), —CON(C 1-4  alkyl)(CH 2 ) 2 N(C 1-4  alkyl) 2 , C 1-4  alkyl, and —(CO) 0-1 -(4- to 6-membered heterocycle comprising carbon atoms and 1-4 heteroatoms selected from N, NH, N(C 1-4  alkyl), O, and S(O) p ; wherein said heterocycle is substituted with 0-2 R 8 ; 
         R 8  is, independently at each occurrence, selected from the group consisting of: halogen, OH, CHF 2 , CF 3 , C 1-4  alkoxy, and C 1-4  alkyl; and 
         p is, independently at each occurrence, selected from the group consisting of: 0, 1, and 2. 
       
     
     
       4. The compound of  claim 3 , having Formula (II), a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L 1  is independently selected from the group consisting of: a bond, —CH 2 CH 2 —, —CH═CH—, —C(Me)═CH—, —C≡C—, and —CH 2 NH—; 
 L is independently selected from the group consisting of: —(CH 2 ) 1-2 -(phenylene)-(CH 2 ) 0-3 —, —CH 2 O(CH 2 ) 1-4 -(phenylene)-(CH 2 ) 0-3 —, —(CH 2 ) 1-2 -(phenylene)-CONH(CH 2 ) 0-2 —, —(CH 2 ) 1-2 -phenylene-CON(C 1-4  alkyl)(CH 2 ) 0-2 —, —(CH 2 ) 1-2 -(pyridinylene)-(CH 2 ) 0-3 —, —CH 2 -pyrimidinylene-(CH 2 ) 0-3 —, 
 
       
         
           
           
               
               
           
         
       
       wherein each ring moiety is substituted with 0-2 R 7a ;
 Y is independently selected from the group consisting of: CH 2 , CH(C 1-4  alkyl), C(C 1-4  alkyl) 2 , O, S, NH, N(C 1-4  alkyl), N(CO 2 (C 1-4  alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4  alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—; 
 R 1  is, independently at each occurrence, selected from: halogen, CN, OH, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , C 1-4  alkyl, C 1-4  alkoxy, CO(C 1-4  alkyl), NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , —C(═NH)NH 2 , —C(O)NH 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4  alkyl), and —SO 2 NH 2 ; 
 R 3  is independently selected from the group consisting of: H, halogen, OH, NH 2 , CN, CF 3 , C 1-4  alkyl, C 1-4  alkoxy, —CH 2 OH, CO 2 H, CO 2 (C 1-4  alkyl), —C(O)NH 2 , —C(O)NH(C 1-4  alkyl), —C(O)N(C 1-4  alkyl) 2 , and —CH 2 CO 2 H; and 
 R 6  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4  alkyl), —CH 2 CO 2 H, —(CH 2 ) 2 CO 2 H, —CH 2 CO 2 (C 1-4  alkyl), —(CH 2 ) 2 CO 2 (C 1-4  alkyl), NH 2 , —CH 2 NH 2 , —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 3 O(C 1-4  alkyl), —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 NH 2 , —NHCO 2 CH 2 CO 2 H, —CH 2 NHCO 2 (C 1-4  alkyl), —NHC(O)NH(C 1-4  alkyl), —NHC(O)N(C 1-4  alkyl) 2 , —NHSO 2 (C 1-4  alkyl), —SO 2 NH(CH 2 ) 2 OH, —SO 2 NH(CH 2 ) 2 O(C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , and 
 
       
         
           
           
               
               
           
         
       
     
     
       5. The compound of  claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L 1  is independently selected from the group consisting of: a bond, —CH 2 CH 2 — and —CH═CH—; 
 R 1  is, independently at each occurrence, selected from the group consisting of: halogen, CN, C 1-4  alkyl, OH, C 1-4  alkoxy, CH 2 F, CHF 2 , CF 3 , OCH 2 F, OCHF 2 , OCF 3 , CO(C 1-4  alkyl), NH 2 , NH(C 1-4  alkyl), N(C 1-4  alkyl) 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4  alkyl), and —C(═NH)NH 2 ; 
 R 3  is independently selected from the group consisting of: H, halogen, CN, CF 3 , CO 2 H, CO 2 (C 1-4  alkyl), and C 1-4  alkyl; and 
 R 6  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, CN, OH, CF 3 , CO 2 H, CO 2 (C 1-4  alkyl), —CH 2 CO 2 H, —CH 2 CO 2 (C 1-4  alkyl), NH 2 , —CH 2 NH 2 , —NHCO(C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —CH 2 NHCO 2 (C 1-4  alkyl), —CONH 2 , —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 CH 2 CO 2 H, —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), and 
 
       
         
           
           
               
               
           
         
       
     
     
       6. The compound of  claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt, a solvate thereof, wherein:
 L is independently selected from the group consisting of: —CH 2 -phenylene-(CH 2 ) 0-3 —, —CH 2 O(CH 2 ) 2-4 -phenylene-(CH 2 ) 0-1 —, —CH 2 -phenylene-CONH(CH 2 ) 0-2 —, —CH 2 -phenylene-CON(C 1-4  alkyl)(CH 2 ) 0-2 —, —CH 2 -pyridinylene-(CH 2 ) 0-3 —, —CH 2 -pyrimidinylene-(CH 2 ) 0-2 —, 
 
       
         
           
           
               
               
           
         
       
       wherein each ring moiety is substituted with 0-1 R 7a ;
 Y is independently selected from the group consisting of: CH 2 , O, NH, N(C 1-4  alkyl), N(CO 2 (C 1-4  alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4  alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—; and 
 L 1  is independently selected from the group consisting of: a bond and —CH═CH—; 
 R 1  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, OH, C 1-4  alkoxy, CO(C 1-4  alkyl), CN, CH 2 F, CHF 2 , OCHF 2 , NH 2 , N(C 1-4  alkyl) 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4  alkyl), and —C(═NH)NH 2 ; 
 R 3  is independently selected from the group consisting of: H, halogen, C 1-4  alkyl, and CN; 
 R 6  is, independently at each occurrence, selected from the group consisting of: halogen, NH 2 , CO 2 H, CO 2 (C 1-4  alkyl), CONH 2 , CONH(C 1-4  alkyl), CON(C 1-4  alkyl) 2 , —NHCO 2 (C 1-4  alkyl), —CH 2 NHCO 2 (C 1-4  alkyl), —NHCO 2 CH 2 CO 2 H, —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), and 
 
       
         
           
           
               
               
           
         
       
       and
 R 7a  is independently selected from the group consisting of: halogen, C 1-4  alkyl, and N(C 1-4  alkyl) 2 . 
 
     
     
       7. The compound of  claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L is independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each ring moiety is substituted with 0-1 R 7a ;
 Y is independently selected from the group consisting of: CH 2 , O, NH, N(C 1-4  alkyl), N(CO 2 (C 1-4  alkyl)), —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4  alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—; 
 L 1  is independently selected from the group consisting of: a bond and —CH═CH—; 
 R 1  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, OH, C 1-4  alkoxy, CO(C 1-4  alkyl), CN, CH 2 F, CHF 2 , OCHF 2 , NH 2 , N(C 1-4  alkyl) 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4  alkyl), and —C(═NH)NH 2 ; 
 R 2  is independently a 5-membered heterocycle selected from: triazolyl and tetrazolyl; 
 R 3  is independently selected from the group consisting of: H, halogen, C 1-4  alkyl, and CN; 
 R 6a  is independently selected from the group consisting of: H, halogen, NH 2 , CO 2 H, CONH 2 , CO 2 (C 1-4  alkyl), —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 CH 2 CO 2 H, —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), and 
 
       
         
           
           
               
               
           
         
       
       and
 R 7a  is independently selected from the group consisting of: halogen, C 1-4  alkyl, and N(C 1-4  alkyl) 2 . 
 
     
     
       8. The compound of  claim 3  or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L is independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein each ring moiety is substituted with 0-1 R 7a ;
 Y is independently selected from the group consisting of: CH 2 , O, NH, —CONH—, —NHCO—, —CONHCH 2 —, —CON(C 1-4  alkyl)CH 2 —, —OCONH—, —NHCONH—, and —SO 2 NH—; 
 L 1  is independently selected from the group consisting of: a bond and —CH═CH—; 
 R 1  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, OH, C 1-4  alkoxy, CO(C 1-4  alkyl), CN, CH 2 F, CHF 2 , OCHF 2 , —CH 2 NH 2 , —CH 2 NHCO 2 (C 1-4  alkyl), and —C(═NH)NH 2 ; 
 R 3  is independently selected from the group consisting of: H, halogen, C 1-4  alkyl, and CN; 
 R 6a  is independently selected from the group consisting of: H, halogen, NH 2 , CO 2 H, CONH 2 , —NHCO 2 (C 1-4  alkyl), —NHCO 2 (CH 2 ) 2 OH, —NHCO 2 (CH 2 ) 2 O(C 1-4  alkyl), —NHCO 2 CH 2 CH(C 1-4  alkyl)O(C 1-4  alkyl), and 
 
       
         
           
           
               
               
           
         
       
       and
 R 7a  is independently selected from the group consisting of: halogen, C 1-4  alkyl, and N(C 1-4  alkyl) 2 . 
 
     
     
       9. The compound of  claim 3 , or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L-Y is independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       wherein each ring moiety is substituted with 0-1 R 7a ;
 L 1  is independently selected from the group consisting of: a bond and —CH═CH—; 
 R 1  is, independently at each occurrence, selected from the group consisting of: halogen, C 1-4  alkyl, C 1-4  alkoxy, CO(C 1-4  alkyl), CN, CHF 2 , and OCHF 2 ; 
 R 2  is independently a 5-membered heterocycle selected from: pyrazolyl, imidazolyl, triazolyl, and tetrazolyl; 
 R 3  is independently selected from the group consisting of: H and halogen; 
 R 6a  is independently selected from the group consisting of: H, halogen, NH(C 1-4  alkyl), and NHCO 2 (C 1-4  alkyl); and 
 R 7a  is independently selected from the group consisting of: halogen, C 1-4  alkyl, N(C 1-4  alkyl) 2 . 
 
     
     
       10. The compound of  claim 9  or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L-Y is independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
       
       wherein each ring moiety is substituted with 0-1 R 7a ;
 R 2  is independently triazolyl or tetrazolyl; and 
 R 6a  is independently selected from the group consisting of: H, halogen, and NHCO 2 (C 1-4  alkyl). 
 
     
     
       11. The compound of  claim 9  or a stereoisomer, a tautomer, a pharmaceutically acceptable salt thereof, wherein:
 L-Y is independently selected from the group consisting of: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 1  is independently selected from the group consisting of: F, Cl, Me, OMe, COMe, CN, CHF 2 , and OCHF 2 ; 
         R 2  is tetrazolyl; 
         R 3  is independently selected from the group consisting of: H and Cl; and 
         R 6a  is independently selected from the group consisting of: H, F, and NHCO 2 Me. 
       
     
     
       12. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and at least one of the compounds of  claim 1 .